DOES A SPONTANEOUS CURE FOR CHAGAS DISEASE EXIST?

Transcrição

1 Revista da Sociedade Brasileira de M edicina Tropical 21(1): 15-20, Jan-M ar, DOES A SPONTANEOUS CURE FOR CHAGAS DISEASE EXIST? Rodrigo Zeledón1, João Carlos P. Dias2, A. Brilla-Salazar3, J. Marcondes de Rezende4, Luis G. Vargas1 and Andrea Urbina1. S ix Costa Rican Chagas disease patients, with wellknown acute phase history and no specific treatment were exam ined in several occasions during 39, 24, 32, 16 and 14 years, respectively, from the onset. N om e o f the patients presented heart abnormalities as revealed by the conventional E K G and ergometry, exceptfor one o f them with an incomplete block o f the right bundle branch. Also, no alterations o f the oesophagus motility was detected manometrically except fo r another patient who presented a slight hypersensivity reaction to a pharmacological test (Mecholyl). Three out o f six patients became serologically negative in 1981, remaining as such until Besides the conventional serology, the search o f protective ( lytic ) antibodies was also performed in 1985 and 1986, being completely negative in one o f the cured patients and dubious in the other two. The hypothesis that these three patients had as spontaneous cure, based on the clinical, serological and parasitologica l findings is discussed. Key words: American trypanosomiasis. Chagas disease. Spontaneous cure. Longitudinal studies. Chagas disease, or American trypanosomiasis, is endemic in most Latin American countries where it is transmitted by several species of triatomine bugs. Its incidence and prevalence varies within different geographical areas and this seems to be related, as least in part, to the relative abundance, within a house, of the particular species of vector involv e d After an acute phase, which is not always detected, a chronic phase is stablished. In some cases it may take as long as 20 years after the acute onset for the pathological manifestations to appear (e.g. alterations of the heart or the digestive tract)2 8 JO Since all patients in the asymptomatic or indeterminate phase remain serologically positive for the specific antigen, they have been considered potential victims for the tissue damage that leads to the different manifestations of the disease In the following paragraphs we present evidence supporting current observations that several patients 1. Proyecto de Zoonosis, Escuela de Medicina Veterinária, Universidad Nacional, Heredia, Costa Rica. 2. Fundação Oswaldo Cruz & Universidade Federal de Minas Gerais. Divisão de Doença de Chagas, SUCAM, Ministério da Saúde, Brasília, D F, Brasil. 3. Servicio de Cardiologia, Hospital México, San José, Costa Rica. 4. Faculdade de Medicina, U.F. Goiás, Goiânia, GO, Brasil. Endereço: João Carlos Pinto Dias. SUCAM, Ministério da Saúde, Esplanada dos Ministérios, Bloco G, anexo A, Brasília. Recebido para publicação em 8/6/87. who had an evident acute phase and no specific chemotherapy remain asymptomatic for long periods of time. Also, as a new hypothesis, that some of them may suddenly become serologically negative suggesting that they evolve towards spontaneous cure of the infection M ETH O D O LO G Y A N D HISTORY OF TH E CASES In a general way this work is a part of epidemiological studies about Chagas disease that have been carried out in Costa Rica since several years by one of us (Z.). The clinic and laboratorial follow-up of some cases that have presented a typical acute phase constitute a routine that includes physical examination, electro-cardiogram (EK G ), X-ray of the chest, xenodiagnoses and conventional serology The xenodiagnoses were initially performed with about 10 third instar nymphs of Triatoma dimidiata, but after 1981 Dipetalogaster m axim a was introduced ( 10 or 20 first instar nymphs per patient). Conventional serologic tests to detect IgG antibodies anti T. cruzi were performed in C osta Rica and foreign laboratories, utilizing four common tests: complement fixation tests (CFT), indirect hemagglutination (IH T), indirect immunofluorescence (IIFT ) and direct agglutination (DAT). All the sera were collected by venous punction and preserved in deep freezers (-20 C). Transportation for other countries was made in ice, by airplane. The used serologic techniques are described by Guim arães14. Non-conventional serology was also applied in order to look for protective or lytic antibodies, in René Rachou Centre, Belo Horizonte, Brazil, by 15

2 ZeledonR, DiasJCP, Brilla-Salazar A, Vargas LG, Urbina A. D o e s a spontaneous cure fo r Chagas disease exist? Revista da Sociedade Brasileira de Medicina Tropical 21:15-20, Jan-Mar, 1988 Drs. A. Krettli and Z. Brener. The technique utilized was immunofluorescence with living trypomastigotes test (ITLT), consisting of treating living T. cruzi trypomastigotes pre-incubated with diluted sera in the presence of sodium azide at 4 C then washed and fixed, plus a fluorescein-conjugated IgG 17. In order to detect incipient chagasic lesions of the heart and oesophagus, in 1983 and 1984 these patients were respectively submitted to ergometric tests, oesophagus manometry and mecholyl tests Ergometry was performed in a conventional track apparatus, through progressive tests monitorized by EKG and blood pressure11. Mecholyl test is a pharmacological technique that employs a cholinergic stimulus (metacholine chloride N.F.) which is able to put in evidence some alterations of the oesophagus intrinsic innervation In the following summarized description the main objective is to characterize the acute phase and the clinical and laboratorial evolution of each case. All the six cases presented a typical picture of acute Chagas disease and four of them had the Romana sign. The direct blood examination was positive for T. cruzi in five patients, while xenodiagnoses were positive in all of them during the acute onset. The patient whose direct examination was negative was M.C.Ch. (case n. 2). She entered the hospital with fever, splenomegaly, tachicardia and generalized oedema. Acute Chagas disease was suspected by Dr. Arturo Romero, being confirmed by xenodiagnosis28. Triatoma dimidiata was found in the houses of all the patients. None of these patients had never received specific treatment against T. cruzi. More detailed information on clinical and laboratorial findings of these cases as well as epidemiological data related to them were presented in different publications Table 1 summarizes the main clinical, epidemiological and laboratorial data concerning this group of patients. Table 2 presents the traditional serology performed in 1985 and 1986 and table 3 shows the results of non-conventional serology (ITLT). 16

3 ZeledonR, DiasJCP, Brilla-SalazarA, Vargas LG, Urbina A. Does a spontaneous cure fo r Chagas disease exist? Revista da Sociedade Brasileira de M edicina Tropical 21:15-20, Jan-M ar, 1988 Table 2 -R ecent results o f Costa Rican patients with two conventional serologic techniques do detect specific anti-t. cruzi antibodies* Patients 10/12/ /06/1986 Final Final N p (initials) IIFT IH T IIFT IH T Interpretation 1 M.C.R.M. Neg. (1:20) Neg. 1:8 1 8 Negative 2 M.C.Ch. 1: 1,024 Pos. 1: Positive 3 F.B. Neg. Neg. Neg Negative 4 J.R.M.A. Neg. Neg. 1:8 1 8 Negative 5 M.A. 1:256 Pos. 1: Positive 6 F.Ch.V. 1:512 1:16 1: Positive IIFT: Indirect immunofluorescence test. IHT: Indirect haemagglutination test. * Serology performed by the Seroepidemiology Laboratory. Ezequiel D ias Foundation, Belo Horizonte, Brazil (Dr. Hélène D Hooge). Table 3 - Chagas disease. Results o f three testsperfomed in Costa Rican sera with the non-conventional immunofluorescence technique made with living trypomastigotes, 1986 N. Patients: (initials) Test 1 Results Test 2 Test 3 Final Interpretation 1 M.C.R.M. Posit. Negat. Dubious Dubious 2 M.C.Ch. Negat. Posit. Posit. Positive 3 F.B. Negat. Negat. Negat. Negative 4 J.R.M.A. Posit. Dubious Negat. Dubious 5 M.A. Posit. Posit. Posit. Positive 6 F.Ch.V. Posit. Posit. Posit. Positive * Sera performed in the laboratories of René Rachou Research Centre, Belo Horizonte, M G, Brazil (Drs. Zigman Brener & Antoniana U. Krettli). D ISCU SSIO N The fact that three of this special group of six Costa Rican patients became serologically negative after a certain period of time is a strong evidence, in our opinion, that they evolved towards a spontaneous cure. It is important to note that all these patients have a well documented acute phase and never received specific treatment for Chagas disease. More over all of them have been clinically well during all the period after the acute disease, none of them presenting any evidence of immunodépression6. The persistent and definitive reversion of the serology from positive to negative results is considered nowadays as the most important cure criterion of human Chagas disease Sporadic negative tests can be observed in a few chronic non-treated patients, sometimes in the very same day in wich xenodiagnoses was found to be positive Nevertheless, this fact is exceptional in longitudinal studies in endemic areas where normally the serological tests become positive again in further observations In experimental laboratory models spontaneous cure of T. cruzi infections was recently observed in opossuns, with persistent negative parasitological and serologieai tests (including the research of lytic antibodies By another way the revertion of the serological tests to negative results has been observed in human chagasic patients treated with specific chemoterapy in the acute phase There is evidence that cured and/or non infected individuals do not present immunoglobulins directed to epitopes expressed on the membrane of living trypomastigotes. Such immunoglobulins are the same protective antibodies responsible for the acquired resistance displayed by the infected host These functional antibodies may disappear 5-7 months after a succesfull treatment, while conventional serolo 17

4 ZeledonR, DiasJCP, Brilla-SalazarA, Vargas LG, Urbina A. Does a spontaneous cure fo r Chagas disease exist? Revista da Sociedade Brasileira de M edicina Tropical 21:15-20, Jan-Mar, 1988 gy can persist positive for up to 4 years in such cases7 17. It is important to observe that our cases n. 1,3 & 4 have shown negative results for conventional serology since 1981, after many examinations and using different techniques. The litres about 8 in some recent tests of the patients np 1 & 4 are very inespecific and must be considered negatives according to current experience1317 The diagnostic value of non-conventional serology is very high, chiefly considering the negative results (sensibility)6 17. Some operational problems with false positive sera may exist and may have occurred in our patients N. s 1 and 4 (Table 3). It has been frequently found some dubious results, mainly in periods immediatly before the definitive convertion of the test to negative outcomes717. F or the patientn? 3 both conventional and non-conventional methods showed consistent negative results, what strongly suggest the possibility of spontaneous cure recently pointed out by Luquetti19 the same possibility exists for the patients N.os 1 & 4, whose conventional serology have persisted negative for 6 years or more. It is convenient to follow these patients for at least further two or three years in order to analyse the real behaviour of their clinical and immunological pictures7 17. N e vertheless the case NP 3 at once can be. considered cured, fact that certainly represents and exception in the natural history of human Chagas diseases The patients n. 2,5 & 6 still present positive serology and correspond to the absolute majority of the cases that are being studied in endemic areas and longitudinal studies None of those cases have shown any important pathological alteration attributable to the disease respectively after 39, 34 and 32 years. They remain in the so called indeterminate form of chronic Chagas disease and present a very good prognosis The border-line alterations observed in the EK G of patient N? 1 and the mecholyl test of patient N? 4 are not to be considered as signs of active Chagas disease2 50, since both alterations can be seen in noninfected people as well as in chagasic people due to residual lesions occurred in the past In the specific case of hypersensitivity to the mecholyl test it only represents a moderate denervation of the intrinsic para-sympathetic plexus of the oesophagus, independently of the aetiological factor Chagas disease in Costa Rica has been well demonstrated in several publications, with a serological prevalence of 11.7% in a group of 1,420 people from an area infested with Triatoma dim idiata34. Some local peculiarities such as the absent (or extremely low) prevalence of digestive mega syndromes are being now studied in the same regional difference context of Chagas disease This paper suggest that some patients could evolve to spontaneous cure of Chagas disease after many years of active infection. It remains to be demonstrated whether this phenomenon, here reported for Costa Rican patients also occurs in other Latinamerican areas where this trypanosomiasis is endemic. This possibility has recently been considered by Arribada et al in Chile4 and Luquetti, in Brazil19, but how frequent the fact occurs and the reason of that occurrence remain to be investigated. RESU M O Um grupo de pacientes com doença de Chagas vem sendo acompanhado desde a fa se aguda, na Costa Rica, com tempos de evolução entre 14 e 44 anos ( mediana de 32 anos). E m todos a doença aguda fo i bem comprovada, não sendo realizado tratamento específico em nenhum deles, contra o Trypanosoma cmzi. Todos apresentaram pelo menos uma sorologia positiva ao longo da fa se crônica, mas em três deles as técnicas sorológicas convencionais se tom aram parmanentemente negativas em diversos exames ealizados em diferentes laboratórios, entre 1981 e Nestes três pacientes tam bém a pesquisa de anticorpos líticos fo i negativa (um caso) ou negativo-duvidosa (dois casos), permanecendo consistentemente positiva nos três outros pacientes com sorologia convencional reagente. Atualm ente todos os seis pacientes se apresentam assintomáticos e com xenodiagnóstico negativo. Apenas um deles apresenta distúrbio eletrocardiogràfico mínimo e inespecífico (bloqueio incompleto do ramo direito) e, um outro, pequeno retardo do trânsito esofagiano à prova de metacolina. Levanta-se a hipótese de cura espontânea da doença de Chagas, fa to que deve ser raro e que merece m aior investigação. Palavras Chaves: Tripanosomiase americana. D oença de Chagas. Cura espontânea. Estudo longitudinal. A C K N O W LED G EM EN TS This work was in part sponsored by a TD R (U N D P/W B /W H O ) grant. W e are grateful to Drs. M ário E. Camargo (Instituto de Medicina Tropical de S. Paulo, Brasil), Jorge E. Yanowsky (Fundación Polychaco, Buenos Aires, Argentina), Zigman Brener and Antoniana U. Krettli (Centro de Pesquisas René Rachou, Belo Horizonte, Brasil) and Hélène D Hooge (Fundação Ezequiel Dias, Belo Horizonte, Brasil) for their precious help with the serology, and to Dr. Phillip D. Marsden (Universidade de Brasilia), for the revision of the manuscript. 18

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